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PubMed2001

Aberrant expression of cyclin D1 in pulmonary proliferative lesions induced by high doses of urethane in transgenic mice carrying the human prototype c-H-ras gene.

In our previous study, when rasH2 mice and non-transgenic (non-Tg) littermates were injected intraperitoneally with 1,000 mg/kg of urethane once or three times at two-day intervals, the incidence of lung proliferative lesions in rasH2 mice given triple doses of urethane was significantly increased, compared to that in rasH2 mice given a single dose of urethane, and the mutation frequency of the transgene in lung tumors in rasH2 mice given triple doses was lower than that in rasH2 mice given a single dose of urethane. In the present study, differential immunohistochemical expressions of Cyclin D1 and PCNA, that lead to abnormal cell proliferation and tumor development due to uncontrolled G1-S transition in the cell cycle, as well as p53 tumor suppressor gene in pulmonary proliferative lesions obtained from our previous study were investigated. Over-expression of Cyclin D1 in hyperplasias in rasH2 mice given triple doses was significantly increased, compared to that in the single-injection group, but no significant differences in Cyclin D1 between the single and triple injection groups were observed in hyperplasias in non-Tg mice or lung tumors in either rasH2 or non-Tg mice. There were no differences in the PCNA labeling index of hyperplasias in rasH2 or non-Tg mice between the triple-injection and single-injection groups, while the PCNA labeling index tended to be increased in the tumor, compared with that in hyperplasias. There was neither mutation of p53 nor an increase in immunoreactivity of wild type p53 in these proliferative lesions. These results suggest that cyclin D1 over-expression in alveolar/bronchiolar hyperplasias in rasH2 mice in the triple-injection group is not only indicative of a high cell proliferation rate but also of an important role in the process of malignant transformation.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1986

Neovascularization in urethane rat retinopathy demonstrated by thymidine labelling.

Rat urethane retinopathy produces sequential and progressive loss of the photoreceptor cells, proceeding from the posterior to the peripheral retina. The inner retina, the retinal pigment epithelium and the choriocapillaris are spared. After loss of the photoreceptor cells, a vasculopathy develops which includes progressive retinal capillary loss and formation of coil-like tufts of retinal vessels which are embedded in the retinal pigment epithelium. Some of the retinal vessels within the retinal pigment epithelium have changed their phenotype from continuous to fenestrated endothelial cells. To elucidate whether DNA synthesis was necessary for formation of the coil-like vessel tuft formation, an autoradiographic study was performed. At 12, 14, 16 and 20 weeks of age, times during which the vasculopathy is known to be forming, urethane and control rats were injected with 3 successive doses of methyl-3H-thymidine. Autoradiography of trypsin-digested retinal vessel preparations was compared with histological sections of the paired eye. The frequency of tritium labelled endothelial cells was much higher in the urethane rats than control animals, and were predominantly in the posterior pole, rather than the periphery. Labelled endothelial cells tended to be associated with, or near, the coil-like vessel tufts. Capillary dropout was observed in urethane, but not control animals. Frequently, adjacent endothelial cells were labelled, suggestive of mitosis. The occurrence of thymidine uptake and a change in phenotype of the endothelial cells leads us to suggest that new cell synthesis, or neovascularization, has occurred in these vessels. Since the retina is less than half the normal thickness and the choriocapillaris is intact, it appears unlikely that ischemia is responsible for inducing these pathological responses. We suggest that the retinal pigment epithelial cell is responsible for the increase in DNA synthesis and change in phenotype of the retinal endothelial cell.

Animals↗
PubMed1991

Activation of the rasHa gene in urethane-initiated papillomas induced by protocols with high and low frequencies of malignant conversion.

The number of papillomas that develop in mice initiated with a single exposure to urethane and promoted by repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) is increased greater than 4-fold by pretreating the skin once with TPA 24 hr before administration of urethane. In contrast, the carcinoma incidence was increased only 2-fold by the TPA pretreatment. Individual papillomas developed from the two protocols, differing in the potential for conversion to malignancy, were compared for activation of the rasHa gene. An activated oncogene that transformed 3T3 cells was found in the DNA of four of five papillomas from urethane-initiated, TPA-promoted mice and in eight of eleven papillomas from similarly promoted mice exposed to TPA before urethane initiation. Southern analysis of DNA from tumors or 3T3 foci demonstrated that the rasHa gene was activated by an A----T transversion at the second base of codon 61 in all mutated alleles. Thus, tumors induced by the two protocols did not differ in rasHa activation.

3T3 Cells↗
PubMed2000

Urethane-induced hyperglycemia.

AIM: To study the effects of urethane, at anesthetic dose, on the blood glucose levels in normal rats and hyperglycemic rats, and its effects on the hypoglycemic action of exogenous insulin in alloxan-treated rats. METHODS: Blood glucose concentration was measured with the glucose oxidase method. RESULTS: Urethane at anesthetic dose 1.5 g.kg-1 increased the blood glucose levels in fasting (to 2.6 +/- 0.3 g.L-1, P < 0.01) or glucose-loaded (to 3.9 +/- 0.4 g.L-1, P < 0.01) rats. It did not modify the hyperglycemia induced by epinephrine (normal islet beta-cells) or alloxan (impaired islet beta-cells). In the rats treated with alloxan, blood glucose level decreased to 1.8 +/- 0.7 g.L-1 at 200 min after administration of insulin from control level of 7.0 +/- 2.3 g.L-1, but the hypoglycemic action of exogenous insulin was abolished by urethane. CONCLUSION: Hyperglycemic action of urethane was due to its inhibiting effect on the hypoglycemic effect of insulin, except for its known mechanism of increased sympathetic release.

Alloxan↗
PubMed1992

Synthesis and antitumor activity of poly(ethylene glycol)s linked to 5-fluorouracil via a urethane or urea bond.

In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects and exhibiting strong antitumor activity, 5FU was covalently linked to poly(ethylene glycol) (PEG) via a urethane or urea bond. For the purpose of evaluating the release behavior of 5FU, the hydrolysis of the urethane or urea bond in the obtained conjugate of PEG-end capped with 5FU was investigated in vitro at 37 degrees C in aqueous solution media. The survival effect for the conjugate was assessed in vivo against p388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (i.p.) transplantation/i.p. injection. The effects of a hydrophobic hexamethylene spacer group, the end group and the number n of ethylene oxide (EO) units in PEG on the release behavior of 5FU and the survival effect were investigated. The release rate of 5FU from the 5FU-terminated PEG conjugates via urethane or urea bond was very fast. However, it became slow with increasing n of EO units in PEG and was depressed by the introduction of hydrophobic spacer group. The 5FU-terminated PEG conjugates obtained exhibited significant survival effects against p388 leukemia mice i.p./i.p. Especially, the methoxy PEG (n = 113)/urethane/hexamethylene/urea/5FU conjugate showed the strongest survival effect among the synthesized 5FU-capped PEG conjugates via urethane or urea bond compared to free 5FU against p388 leukemia mice. These conjugates obtained did not display an acute toxicity even in high dose ranges.

Animals↗
PubMed1991

The effects of Tordon 202c exposure on urethan-induced lung adenoma formation in female CD-1 mice.

Female CD-1 mice were exposed to Tordon 202c, a herbicide containing 2,4-dichlorophenoxyacetic acid and picloram, in the drinking water for 15 w at concentrations ranging from 0 to 0.3% of the product formulation. After 3 w of the 15-w treatment period, the mice received 1.5 mg/g urethan ip. Pulmonary adenoma production was evaluated 12 w later. Tordon 202c exposure produced a dose-dependent increase in tumor number, but had no effect on tumor size. Urethan-induced sleeping times which reflected the rate of urethan metabolism or excretion were altered, but a specific dose-related effect which could be correlated with tumor production was not observed. This suggests that Tordon 202c exposure influences adenoma formation by immunological mechanisms rather than by causing indirect effects on urethan metabolism or excretion.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1990

Sensitivity of subpopulations of mouse skin papillomas to malignant conversion by urethane or 4-nitroquinoline N-oxide.

Papillomas induced in SENCAR mice by initiation with 7,12-dimethylbenz(a)anthracene and promotion by treatment for 10-12 weeks with 12-O-tetradecanoylphorbol-13-acetate (TPA) convert to malignancy at a low frequency. The rate of malignant conversion can be increased by either (a) promoting with TPA for a shorter duration or (b) treatment of papilloma-bearing mice with certain genotoxic chemicals, such as 4-nitroquinoline N-oxide (4-NQO) or urethane. The spontaneous conversion rate of papillomas promoted by 5 weeks of TPA exposure is severalfold higher than that of papillomas arising later during TPA promotion. Here, we compared the sensitivity to the converting agents 4-NQO and urethane of papillomas promoted by TPA for either 5, 10, or 20 weeks. In the mice promoted for 5 weeks with TPA, the already high spontaneous conversion frequency was increased 2.5 times by 4-NQO. A 2-fold increase was found after 10 weeks of TPA promotion. In contrast, no increase was seen with 4-NQO exposure begun after 20 weeks of TPA promotion. Similar results were found with urethane as converting agent. The sensitivity of the papillomas induced by short-term TPA treatment to induced conversion remains high even after a 16-week period without TPA treatment; when urethane exposure was delayed until week 21 after TPA promotion for weeks 1-5, a 2.4-fold increase in the conversion frequency was observed.

4-Nitroquinoline-1-oxide↗
PubMed1987

Urethane-acepromazine: a novel method of administering parenteral anesthesia in the rabbit.

Stable long-term anesthesia in the rabbit (greater than 8 hr) has been achieved by the administration of urethane and acepromazine. Twenty-five healthy male New Zealand white rabbits weighing 2 to 4 kg were used for this study. Two groups of animals were studied. The first group of 11 rabbits received urethane (1.0 g/kg) and acepromazine (1 mg/0.46 kg). This resulted in stable light plane anesthesia for 13.5 +/- 4.5 hr (mean + S.D.). The second group of 14 rabbits received urethane (1.3 g/kg) and acepromazine (1 mg/0.46 kg) which resulted in deep plane anesthesia for 23.0 +/- 4 hr. Heart rate and respiratory rate remained stable throughout the entire period and all animals were alert and without any observable side effects by 48 +/- 3 hr. This study indicates that the combination of urethane-acepromazine is a safe and reproducible parenteral anesthetic that may be used in studies of long duration in rabbits.

Acepromazine↗
PubMed1987

Cellular derivation of lung tumors in sensitive and resistant strains of mice: results at 28 and 56 weeks after urethan treatment.

Urethan (CAS: 51-79-6)-induced pulmonary adenomas that arise from either alveolar type II pneumocytes of bronchiolar Clara cells have distinct histologic growth patterns and can thus be distinguished from each other. Strain differences were reported in the relative proportions of tumors derived from each cell type when these tumors were examined 14 weeks after urethan treatment. For determination as to whether these proportions changed at later stages of growth, tumors in A/J, SWR/J, RIIIS/J, BALB/cByJ, 129/J, and C57BL/6J mice were examined at 28 and 56 weeks after urethan treatment. Tumor multiplicity increased with time in all strains. Small tumors were predominantly type II cell derived in most strains, whereas medium and large tumors were derived mainly from Clara cells. This suggests that type II tumors are restricted in growth while Clara tumors may continue to grow. Medium and large Clara-derived tumors made up a larger proportion of the total tumor population at 28 and 56 weeks than at 14 weeks post urethan, even in A/J mice that typically display 85% type II cell-derived tumors at the earlier time. Several large Clara cell-derived tumors exhibited characteristics of cancer, whereas no type II cell-derived tumor was observed to do so. These results implicate the bronchiolar Clara cell as the predominant cell of origin of pulmonary adenocarcinomas in mice.

Adenoma↗
PubMed1987

The effect of arsenic on urethan-induced adenoma formation in Swiss mice.

Female Swiss mice were exposed to sodium arsenite or sodium aresenate in the drinking water for 15 weeks at concentrations ranging from 0 to 100 micrograms/mL arsenic content. After three weeks of the 15 week exposure period, the mice were administered urethan (1.5 mg/g) intraperitoneally. Pulmonary adenoma formation was evaluated 12 weeks later. Arsenic exposure produced a protective effect with respect to tumor development. Both forms of arsenic reduced the size and number of pulmonary adenomas observed per mouse. In addition, urethan-induced sleeping times which reflect the rate of urethan metabolism or excretion remained unchanged. This suggests that arsenic exposure does not alter urethan excretion and is not a factor influencing subsequent adenoma formation of these levels of exposure.

Adenoma↗
PubMed1987

Alterations in urethan-induced adenoma formation in mice exposed to selenium and arsenic.

Female Swiss were exposed to sodium selenite (3 micrograms/ml selenium content) and sodium arsenate (80 micrograms/ml arsenic content) in the drinking water individually or in combination on alternate days for 15 weeks. Comparable water consumption was observed in all individual or combined metal-exposure groups. After 3 weeks of metal exposure, the mice were administered urethan (1.5 mg/g) intraperitoneally. Pulmonary adenoma formation was evaluated 12 weeks later. Arsenic exposure reduced the tumor incidence (P = 0.0046) and tumor size (P less than 0.0001). Selenium exposure did not alter the tumor incidence but caused a reduction in tumor size (P = 0.022). No selenium-arsenic interactions associated with tumor size or number were observed. Urethan-induced sleeping times were unaffected by exposure to selenium (P = 0.832) or arsenic (P = 0.42), although combined metal exposure reduced the duration of urethan-induced sleep (P = 0.029) as compared to the individual metal exposures. This metal-metal interaction, which appeared to enhance the rate of urethan elimination as indicated by the reduced sleeping time, did not influence adenoma formation significantly.

Adenoma↗
PubMed1985

[Urethane inhibition of DNA synthesis in the hepatocytes of the regenerating liver in mice].

Hepatocarcinogen urethane (ethyl carbamate) inhibits DNA synthesis in the regenerating mice liver when administered at the peak of stimulated proliferation--46 hours after partial hepatectomy. The inhibition is temporary and reversible. The maximum inhibition of 3H-thymidine incorporation in the cells is observed 12 hours after urethane administration, and the effect is removed following 20 hours after administration. Another effect of urethane consists in the lengthening of the period of DNA synthesis by 1.38 times, as estimated by the Quastler-Sherman method, though it does not affect the length of G2-period or mitosis. Possible mechanisms of the effect of urethane on the initiation of DNA synthesis and on the rate of DNA replication are discussed.

Animals↗
PubMed1971

Alteration in cell proliferation in mouse lung following urethane exposure. II. Effects of chronic exposure on terminal bronchiolar epithelium.

Cell proliferation in bronchiolar epithelium of normal mouse lung and of lung chronically exposed to urethane was compared. Animals treated for 10 weeks with drinking water containing 0.1% urethane and their controls were injected with (3)H-thymidine; autoradiographs were made of lung tissue and mean grain counts of labeled nuclei in terminal bronchiolar epithelium compared in the control and urethane-treated groups. In controls, the decline in mean grain counts of labeled daughter cells between 24 hours and 4 days after (3)H-thymidine injection was compatible with a mean cell cycle time of about 60 hours. In contrast, the hyperplastic bronchiolar epithelium of the urethane-treated animals showed an elevated labeling index and deficient production of labeled cells over the 6-day period as judged by decline in mean grain counts. These findings were interpreted as showing that the hyperplasia and high labeling index did not represent faster turnover or shortened cycle but reflected an increase in cell cycle time or of population renewal time.

Adenoma↗
PubMed1984

[Alterations in local cerebral glucose utilization during various anesthesia--the effect of urethane and a review].

Anesthetic is thought to depress the energy metabolism or oxygen consumption of the brain as a whole. It has been clear, however, that anesthetic agent may either decrease or increase local metabolic rate of the brain since [14C] 2-deoxyglucose method made one possible to measure local cerebral glucose utilization. In this paper, the authors report the effect of urethane anesthesia on the local cerebral glucose utilization. We measured local cerebral glucose utilization by means of [14C] 2-deoxyglucose method in 87 brain structures of albino rats (about 300 g) under urethane anesthesia, 1 g/kg (n = 5), and conscious state (n = 6). When the whole brain metabolism was computed as a weighted average with the acid of the computerized image-processing system, there was 33% reduction in glucose utilization of the brain as a whole in the rats under urethane anesthesia. Urethane decreased the local rate of glucose metabolism, but the metabolic effect was not homogeneous throughout the brain. The neural structures in which no metabolic depression was observed were entorhinal cortex, many nuclei in hypothalamus, medial habenula-interpeduncular nucleus, nucleus tractus solitarius, and some white matters. The selective metabolic sparing in the habenula-interpeduncular system was also reported to be observed during chloral hydrate and enflurane anesthesia. However, the mechanism involved in the phenomenon remains unclear. In the discussion, we discussed the differential effects of various anesthetics of the local cerebral glucose utilization. We reviewed the literatures on the effects of various anesthetics; barbiturate, chloralose, chloral hydrate, enflurane, ketamine, nitrous oxide and halothane on the local rate of metabolism of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1983

Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice.

Fewer lung adenomas were induced by urethan in BALB/cBy mice than in the A/J or SWR/J mouse strains. When BALB mice were crossed with either of these more sensitive strains the response of the progeny to urethan was most easily explained by a single gene which regulates susceptibility, with the more resistant phenotype behaving as a dominant trait. C56BL/6J mice were more resistant to adenoma induction than were BALB mice; progeny obtained when these two strains were crossed resembled the BALB susceptibility phenotype. As an approach to understanding the mechanism of action of this gene, agents that modulate adenoma initiation and tumor promotion were tested in BALB mice and other strains. The number of adenomas in BALB mice were increased severalfold by multiple urethan injections, which presumably affect initiation, and by the use of butylated o-hydroxytoulene as a promoting agent. Tumor incidence in A-mice was increased 50% by each treatment; neither procedure caused tumors to appear in the resistant DBA/2J, C3H/-21BG, or C57BL/6J strains. No relationship was observed between the strain dependency of the lethal effects of multiple injections of these agents and the relative susceptibilities of these strains to adenoma induction. The role of certain host factors in the regulation of tumor susceptibility was also tested. Homozygosity for the beige (bg) mutation had no effect on tumor numbers in C57 mice, suggesting that natural killer cells, deficient in bg/bg mice, played no major role in determining adenoma susceptibility in this strain. No correlation was found between the susceptibility of various sublines to urethan-induced lung adenoma and the reported relative tumoricidal capacities of the peritoneal macrophages from these sublines.

Adenoma↗
PubMed1980

[Epithelial proliferative activity of organ cultures of mouse embryonic lungs normally and under the action of urethane].

Autoradiography was used to study the proliferative activity of the epithelium of organ cultures from embryonic mouse lungs in health and under the action of urethane. Highly cancerous A and poorly cancerous C57BI mice in health and under the transplacental action of urethane were used in the experiments. In contradistinction to A mice, the proliferative activity of the epithelium from the lungs of embryonic C57BI mice proved to be stable in organotypical cultivation. Transplacental exposure to urethane in vivo induced the decreased label index only in the epithelium from the lungs of embryonic A mice. The character of the growth stimulating action of urethane and other carcinogens as well as possibility of using this criterion as rapid test for carcinogenicity and estimation of the biological subject predisposition to tumor arousal are discussed.

Animals↗
PubMed1997

Contrasting effects of urethane, ketamine, and thiopental anesthesia on ethanol-clonidine hemodynamic interaction.

In previous studies, we have shown that ethanol counteracts the hypotensive and sympathoinhibitory effects of clonidine in conscious rats but enhances these responses in alpha-chloralose anesthetized rats. This study investigated whether the latter finding pertains to other anesthetics that act by different mechanisms. The hemodynamic interaction between clonidine and ethanol was evaluated in conscious aortic barodenervated rats and in rats anesthetized with urethane, ketamine, or thiopental. The conscious aortic barodenervated rat was used because it exhibits a greater hypotensive response to clonidine compared with intact (sham-operated) rats. Starting from similar baseline values of blood pressure (BP) and heart rate, clonidine (30 micrograms/kg, iv) elicited similar decreases in BP in all groups of rats (conscious aortic barodenervated or anesthetized). Subsequent administration of ethanol (1 g/kg, iv) counteracted the hypotensive effect of clonidine in conscious aortic barodenervated rats and raised the BP to levels higher than the baseline (preclonidine) values. The pressor effect of ethanol persisted for at least 30 min. In contrast, preadministration of ethanol had no effect on the hypotensive effect of the subsequently administered clonidine. The antagonistic clonidine-ethanol hemodynamic interaction in conscious rats was not altered in urethane-anesthetized rats, both in terms of magnitude and duration. In ketamine-anesthetized rats, a short lasting (< 10 min) pressor effect of ethanol was observed. In contrast, ethanol augmented the hypotensive effect of clonidine in thiopental-anesthetized rats; the hypotensive effect of clonidine became slightly but significantly (p < 0.05) greater after ethanol compared with respective time control values. These findings suggest that the adverse hemodynamic effect of ethanol on centrally mediated hypotensive response is modified by different anesthetics. The antagonistic hemodynamic interaction, demonstrated in conscious rats, is replicated in urethane-anesthetized rats but weakened and reversed in ketamine- and thiopental-anesthetized rats, respectively. Therefore, urethane-anesthetized rats may be used in mechanistic studies on the antagonistic ethanol-clonidine hemodynamic interaction that cannot be undertaken, for technical reasons, in conscious rats.

Anesthetics, Dissociative↗
PubMed1977

[Effect of the tissue-specific lung adhesive factor on the urethane induction of pulmonary adenomas in mice].

The effect of adhesive factor (AF), urethane and their combination on the mechanical properties of lung tissue (this effect was assessed by the nuclei isolation during a standard dispersion procedure) and on adenoma induction was studied. As shown, the AF doses eliminating the primary action of urethane on the mechanical properties of the tissue significantly decreased the incidence of adenomas. High AF doses producing a contrary effect on the mechanical properties of the tissue failed to eliminate the primary effect of urethane and did not decrease the number of adenomas induced by urethane.

Adenoma↗